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Publication numberUS9623264 B2
Publication typeGrant
Application numberUS 14/704,270
Publication date18 Apr 2017
Filing date5 May 2015
Priority date24 Aug 2011
Also published asEP2747728A2, EP2747728A4, US8594783, US8774914, US9050463, US20130053905, US20140058295, US20140276249, US20150246248, US20170209697, WO2013028262A2, WO2013028262A3
Publication number14704270, 704270, US 9623264 B2, US 9623264B2, US-B2-9623264, US9623264 B2, US9623264B2
InventorsTimothy Andrew WAGNER
Original AssigneeHighland Instruments
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Systems and methods for stimulating cellular function in tissue
US 9623264 B2
Abstract
The invention generally relates to systems and methods for stimulating cellular function in biological tissue. In certain embodiments, the invention provides a method for stimulating cellular function within tissue that involves providing a first type of energy to a region of tissue, in which the first type is provided in an amount that inhibits cellular function within the region of tissue, and providing a second type of energy to the region of tissue, in which the second type is provided in an amount that facilitates cellular function within the region of tissue, wherein the combined effect stimulates cellular function within the tissue.
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Claims(32)
What is claimed is:
1. A method for treating an arthritic condition, the method comprising:
providing an electrical type of energy to a location in a region of neural tissue; and
providing a non-electrical type of energy to the location in the region of neural tissue;
wherein one type is provided in an amount that inhibits cellular function within the location in the region of neural tissue, the other type is provided in an amount that facilitates cellular function within the location in the region of neural tissue, and the combined effect stimulates cellular function within the neural tissue in a manner in which the stimulatory effect exceeds the combined effect of the two amounts of energy provided to the region of tissue, thereby reducing or eliminating symptoms of the arthritic condition.
2. The method according to claim 1, wherein the stimulatory effect is facilitatory to the cellular function within the tissue.
3. The method according to claim 1, wherein the stimulatory effect is inhibitory to the cellular function within the tissue.
4. The method according to claim 1, wherein the electrical and non-electrical types are provided simultaneously.
5. The method according to claim 1, wherein the electrical and non-electrical types are provided sequentially.
6. The method according to claim 1, wherein the non-electrical type of energy is a mechanical type of energy.
7. The method according to claim 6, wherein the mechanical type of energy is generated by an ultrasound device.
8. The method according to claim 7, wherein the mechanical type of energy is pulsed.
9. The method according to claim 7, wherein the mechanical type of energy is time varying.
10. The method according to claim 7, wherein the mechanical type of energy is pulsed a plurality of times, and each pulse may be for a different length of time.
11. The method according to claim 1, wherein the electric type of energy is pulsed.
12. The method according to claim 1, wherein the electric type of energy is time varying.
13. The method according to claim 1, wherein the electric type of energy is pulsed a plurality of times, and each pulse may be for a different length of time.
14. The method according to claim 1, wherein the electric type of energy is time invariant.
15. The method according to claim 1, wherein the electrical and non-electrical types of energy are applied to a structure or multiple structures within the brain or the nervous system selected from the group consisting of: dorsal lateral prefrontal cortex, any component of the basal ganglia, nucleus accumbens, gastric nuclei, brainstem, thalamus, inferior colliculus, superior colliculus, periaqueductal gray, primary motor cortex, supplementary motor cortex, occipital lobe, Brodmann areas 1-48, primary sensory cortex, primary visual cortex, primary auditory cortex, amygdala, hippocampus, cochlea, cranial nerves, cerebellum, frontal lobe, occipital lobe, temporal lobe, parietal lobe, sub-cortical structures, and spinal cord.
16. The method according to claim 1, wherein the effect of the stimulation alters neural function past the duration of stimulation.
17. A method for treating a skeletal disorder, the method comprising:
providing an electrical type of energy to a location in a region of neural tissue; and
providing a non-electrical type of energy to the location in the region of neural tissue;
wherein one type is provided in an amount that inhibits cellular function within the location in the region of neural tissue, the other type is provided in an amount that facilitates cellular function within the location in the region of neural tissue, and the combined effect stimulates cellular function within the neural tissue in a manner in which the stimulatory effect exceeds the combined effect of the two amounts of energy provided to the region of tissue, thereby reducing or eliminating symptoms of the skeletal disorder.
18. The method according to claim 17, wherein the stimulatory effect is facilitatory to the cellular function within the tissue.
19. The method according to claim 17, wherein the stimulatory effect is inhibitory to the cellular function within the tissue.
20. The method according to claim 17, wherein the electrical and non-electrical types are provided simultaneously.
21. The method according to claim 17, wherein the electrical and non-electrical types are provided sequentially.
22. The method according to claim 17, wherein the non-electrical type of energy is a mechanical type of energy.
23. The method according to claim 22, wherein the mechanical type of energy is generated by an ultrasound device.
24. The method according to claim 23, wherein the mechanical type of energy is pulsed.
25. The method according to claim 23, wherein the mechanical type of energy is time varying.
26. The method according to claim 23, wherein the mechanical type of energy is pulsed a plurality of times, and each pulse may be for a different length of time.
27. The method according to claim 17, wherein the electric type of energy is pulsed.
28. The method according to claim 17, wherein the electric type of energy is time varying.
29. The method according to claim 17, wherein the electric type of energy is pulsed a plurality of times, and each pulse may be for a different length of time.
30. The method according to claim 17, wherein the electric type of energy is time invariant.
31. The method according to claim 17, wherein the electrical and non-electrical types of energy are applied to a structure or multiple structures within the brain or the nervous system selected from the group consisting of: dorsal lateral prefrontal cortex, any component of the basal ganglia, nucleus accumbens, gastric nuclei, brainstem, thalamus, inferior colliculus, superior colliculus, periaqueductal gray, primary motor cortex, supplementary motor cortex, occipital lobe, Brodmann areas 1-48, primary sensory cortex, primary visual cortex, primary auditory cortex, amygdala, hippocampus, cochlea, cranial nerves, cerebellum, frontal lobe, occipital lobe, temporal lobe, parietal lobe, sub-cortical structures, and spinal cord.
32. The method according to claim 17, wherein the effect of the stimulation alters neural function past the duration of stimulation.
Description
RELATED APPLICATIONS

This patent application is a continuation of U.S. nonprovisional patent application Ser. No. 14/293,525, filed Jun. 2, 2014, which is a continuation of U.S. nonprovisional patent application Ser. No. 14/069,613, filed Nov. 1, 2013, which is a continuation of U.S. nonprovisional patent application Ser. No. 13/216,313, filed Aug. 24, 2011, the content of each of which is incorporated by reference herein in its entirety.

GOVERNMENT SUPPORT

This invention was made with Government support under Grant Number R43NS062530 awarded by the National Institute of Neurological Disorders and Stroke (NINDS) of the National Institute of Health (NIH) and Contract No. W31P4Q-09-C-0117 awarded by Defense Advanced Research Projects Agency (DARPA). The Government has certain rights in this invention.

FIELD OF THE INVENTION

The invention generally relates to systems and methods for stimulating cellular function in biological tissue.

BACKGROUND

Stimulation of tissue in humans and other animals is used in a number of clinical applications as well as in clinical and general biological research. In particular, stimulation of neural tissue has been used in the treatment of various diseases including Parkinson's disease, depression, and intractable pain. The stimulation may be applied invasively, e.g., by performing surgery to remove a portion of the skull and implanting electrodes in a specific location within brain tissue, or non-invasively, .e.g., transcranial direct current stimulation and transcranial magnetic stimulation.

SUMMARY

The invention recognizes that a synergistic stimulation effect in a region of tissue may be achieved by combining a first type of energy that is provided in an amount that inhibits cellular function with a second type of energy that is provided in an amount that facilitates cellular function. Data herein show that the stimulatory effect is greater than the summed effect of the first and second amounts of energy provided to the region of tissue.

Accordingly, methods of the invention involve providing a first type of energy to a region of tissue, in which the first type is provided in an amount that inhibits cellular function within the region of tissue, and providing a second type of energy to the region of tissue, in which the second type is provided in an amount that facilitates cellular function within the region of tissue, wherein the combined effect stimulates cellular function within the tissue. In certain embodiments, the stimulatory effect is facilitatory to the cellular function within the tissue. In other embodiments, the stimulatory effect is inhibitory to the cellular function within the tissue. The first and second types of energy may be provided simultaneously or sequentially.

Any energy sources known in the art may be used with systems of the invention. In certain embodiments, the first energy source is an electric source that produces an electric field. The electric filed may be pulsed, time varying, pulsed a plurality of time with each pulse being for a different length of time, or time invariant. In certain embodiments, the second energy source is a source that produces a mechanical field, such as an ultrasound device. The mechanical filed may be pulsed, time varying, or pulsed a plurality of time with each pulse being for a different length of time. In certain embodiments, the electric field and/or the mechanical field is focused. The other permutations are also attainable, where the effect direction (i.e., inhibitory or facilitatory) is dependent on the electrical and/or ultrasound source transducer parameters and/or the electrical and/or ultrasound field parameters.

The first and second energy sources may be applied to any tissue. In certain embodiments, the first and second energy sources are applied to a structure or multiple structures within the brain or the nervous system such as the dorsal lateral prefrontal cortex, any component of the basal ganglia, nucleus accumbens, gastric nuclei, brainstem, thalamus, inferior colliculus, superior colliculus, periaqueductal gray, primary motor cortex, supplementary motor cortex, occipital lobe, Brodmann areas 1-48, primary sensory cortex, primary visual cortex, primary auditory cortex, amygdala, hippocampus, cochlea, cranial nerves, cerebellum, frontal lobe, occipital lobe, temporal lobe, parietal lobe, sub-cortical structures, and spinal cord. In particular embodiments, the tissue is neural tissue, and the affect of the stimulation alters neural function past the duration of stimulation.

Another aspect of the invention provides a system for stimulating cellular function within tissue that includes an ultrasound device configured to emit a mechanical field that inhibits cellular function within the region of tissue, and an electric source configured to emit an electric field that facilitates cellular function within the region of tissue, the system being configured such that the ultrasound device and the electric source target the same region of tissue and the combined effect stimulates cellular function in a facilitatory manner within the region of tissue. Similarly, the ultrasound source could be provided in a facilitatory manner and the electrical source in an inhibitory manner such that the overall effect on cellular function is inhibitory. The other permutations are also attainable, where the effect direction (i.e., inhibitory or facilitatory) is dependent on the electrical and/or ultrasound source transducer parameters and/or the electrical and/or ultrasound field parameters.

BRIEF DESCRIPTION OF THE DRAWINGS

The above-mentioned and other features and objects of this invention, and the manner of attaining them, will become more apparent and the invention itself will be better understood by reference to the following description of embodiments of the invention taken in conjunction with the accompanying drawings, wherein:

FIG. 1 is a plan view of one embodiment of an apparatus for stimulating biological tissue constructed in accordance with the principles of the present disclosure;

FIG. 2 is a top plan view of an exemplary embodiment of an apparatus for stimulating biological tissue constructed in accordance with the principles of the present disclosure;

FIG. 3 is a top plan view of an exemplary embodiment of an apparatus for stimulating biological tissue implementing a chemical source for altering permittivity constructed in accordance with the principles of the present disclosure;

FIG. 4 is a top plan view of an exemplary embodiment of an apparatus for stimulating biological tissue implementing a radiation source for altering permittivity constructed in accordance with the principles of the present disclosure; and

FIG. 5 is a top plan view of another exemplary embodiment of an apparatus for stimulating biological tissue implementing an optical beam for altering permittivity constructed in accordance with the principles of the present disclosure.

FIG. 6 panels A-C show a set of graphs comparing mechanical stimulation alone, electrical stimulation alone, and the combination of mechanical and electrical stimulation. Panel A is a raw data example of visual evoked potentials (VEPs) shown from one animal, and one electrode contact (for readability). Panel B demonstrates the stimulation effect (averaged across all contacts and animals). Panel C demonstrates the depth effect of stimulation (the electrode implemented had 23 contacts (50 mm length, and 50 mm inter-contact distance), but in FIG. 6 panel C only 3 contacts are shown for readability). Throughout the figure, * indicates significance, which was determined first by an N-way Anova, as explained in the examples section, with a subsequent multiple comparison of means (with LSD correction).

DETAILED DESCRIPTION

It is envisioned that the present disclosure may be used to stimulate biological tissue in-vivo comprising an electric source that is placed on and/or in the body to generate an electric field and a means for altering the permittivity of tissue relative to the electric field, whereby the alteration of the tissue permittivity relative to the electric field generates a displacement current in the tissue. The exemplary embodiments of the apparatuses and methods disclosed can be employed in the area of neural stimulation, where amplified, focused, direction altered, and/or attenuated currents could be used to alter neural activity via directly stimulating neurons, depolarizing neurons, hyperpolarizing neurons, modifying neural membrane potentials, altering the level of neural cell excitability, and/or altering the likelihood of a neural cell firing. Likewise, the method for stimulating biological tissue may also be employed in the area of muscular stimulation, including cardiac stimulation, where amplified, focused, direction altered, and/or attenuated currents could be used to alter muscular activity via direct stimulation, depolarizing muscle cells, hyperpolarizing muscle cells, modifying membrane potentials, altering the level of muscle cell excitability, and/or altering the likelihood of cell firing. Similarly, it is envisioned that the present disclosure may be employed in the area of cellular metabolism, physical therapy, drug delivery, and gene therapy. Furthermore, stimulation methods described herein can result in or influence tissue growth (such as promoting bone growth, directing neural growth or regeneration, and/or interfering with a tumor).

Detailed embodiments of the present disclosure are disclosed herein, however, it is to be understood that the described embodiments are merely exemplary of the disclosure, which may be embodied in various forms. Therefore, specific functional details disclosed herein are not to be interpreted as limiting, but merely as a basis for the claims and as a representative basis for teaching one skilled in the art to variously employ the present disclosure in virtually any appropriately detailed embodiment.

The components of the tissue stimulation method according to the present disclosure are fabricated from materials suitable for a variety medical applications, such as, for example, polymerics, gels, films, and/or metals, depending on the particular application and/or preference. Semi-rigid and rigid polymerics are contemplated for fabrication, as well as resilient materials, such as molded medical grade polyurethane, as well as flexible or malleable materials. The motors, gearing, electronics, power components, electrodes, and transducers of the method may be fabricated from those suitable for a variety of medical applications. The method according to the present disclosure may also include circuit boards, circuitry, processor components, etc. for computerized control. One skilled in the art, however, will realize that other materials and fabrication methods suitable for assembly and manufacture, in accordance with the present disclosure, also would be appropriate.

The following discussion includes a description of the components and exemplary methods for generating currents in biological tissues in accordance with the principles of the present disclosure. Alternate embodiments are also disclosed. Reference will now be made in detail to the exemplary embodiments of the present disclosure illustrated in the accompanying figures wherein like reference numerals indicate the similar parts throughout the figures.

Turning now to FIG. 1, which illustrates an exemplary embodiment of an apparatus 10 to alter currents, e.g., amplify, focus, alter direction, and/or attenuate in the presence of an applied electric field or applied current source by the combined application of a mechanical field within a biological material to stimulate the biological cells and/or tissue in accordance with the present disclosure. For example, the apparatus 10 illustrated in FIG. 1 according to the present disclosure may be applied to the area of neural stimulation. An initial source electric field 14 results in a current in the tissue. The electric field 14 is created by an electric source, current or voltage source. As described in further detail below, the permittivity of the tissue is altered relative to the electric field, for example by a mechanical field, thereby generating an additional displacement current.

Electrodes 12 are applied to the scalp and generate a low magnitude electric field 14 over a large brain region. While electrodes 12 are used and applied to the scalp in this exemplary embodiment, it is envisioned that the electrodes may be applied to a number of different areas on the body including areas around the scalp. It is also envisioned that one electrode may be placed proximal to the tissue being stimulated and the other distant, such as one electrode on the scalp and one on the thorax. It is further envisioned that electric source could be mono-polar with just a single electrode, or multi-polar with multiple electrodes. Similarly, the electric source may be applied to tissue via any medically acceptable medium. It is also envisioned that means could be used where the electric source does not need to be in direct contact with the tissue, such as for example, inductive magnetic sources where the entire tissue region is placed within a large solenoid generating magnetic fields or near a coil generating magnetic fields, where the magnetic fields induce electric currents in the tissue.

The electric source may be direct current (DC) or alternating current (AC) and may be applied inside or outside the tissue of interest. Additionally, the source may be time varying. Similarly, the source may be pulsed and may be comprised of time varying pulse forms. The source may be an impulse. Also, the source according to the present disclosure may be intermittent.

A mechanical source such as an ultrasound source 16 is applied on the scalp and provides concentrated acoustic energy 18, i.e., mechanical field to a focused region of neural tissue, affecting a smaller number of neurons 22 than affected by the electric field 14, by the mechanical field 18 altering the tissue permittivity relative to the applied electric field 14, and thereby generating the altered current 20. The mechanical source may be any acoustic source such as an ultrasound device. Generally, such device may be a device composed of electromechanical transducers capable of converting an electrical signal to mechanical energy such as those containing piezoelectric materials, a device composed of electromechanical transducers capable of converting an electrical signal to mechanical energy such as those in an acoustic speaker that implement electromagnets, a device in which the mechanical source is coupled to a separate mechanical apparatus that drives the system, or any similar device capable of converting chemical, plasma, electrical, nuclear, or thermal energy to mechanical energy and generating a mechanical field.

Furthermore, the mechanical field could be generated via an ultrasound transducer that could be used for imaging tissue. The mechanical field may be coupled to tissue via a bridging medium, such as a container of saline to assist in the focusing or through gels and/or pastes which alter the acoustic impedance between the mechanical source and the tissue. The mechanical field may be time varying, pulsed, an impulse, or may be comprised of time varying pulse forms. It is envisioned that the mechanical source may be applied inside or outside of the tissue of interest. There are no limitations as to the frequencies that can be applied via the mechanical source, however, exemplary mechanical field frequencies range from the sub kHZ to 1000s of MHz. Additionally, multiple transducers providing multiple mechanical fields with similar or differing frequencies, and/or similar or different mechanical field waveforms may be used—such as in an array of sources like those used in focused ultrasound arrays. Similarly, multiple varied electric fields could also be applied. The combined fields, electric and mechanical, may be controlled intermittently to cause specific patterns of spiking activity or alterations in neural excitability. For example, the device may produce a periodic signal at a fixed frequency, or high frequency signals at a pulsed frequency to cause stimulation at pulse frequencies shown to be effective in treating numerous pathologies. Such stimulation waveforms may be those implemented in rapid or theta burst TMS treatments, deep brain stimulation treatments, epidural brain stimulation treatments, spinal cord stimulation treatments, or for peripheral electrical stimulation nerve treatments. The ultrasound source may be placed at any location relative to the electrode locations, i.e., within, on top of, below, or outside the same location as the electrodes as long as components of the electric field and mechanical field are in the same region. The locations of the sources should be relative to each other such that the fields intersect relative to the tissue and cells to be stimulated, or to direct the current alteration relative to the cellular components being stimulated.

The apparatus and method according to the present disclosure generates capacitive currents via permittivity alterations, which can be significant in magnitude, especially in the presence of low frequency applied electric fields. Tissue permittivities in biological tissues are much higher than most other non biological materials, especially for low frequency applied electric fields where the penetration depths of electric fields are highest. This is because the permittivity is inversely related to the frequency of the applied electric field, such that the tissue permittivity magnitude is higher with lower frequencies. For example, for electric field frequencies below 100,000 Hz, brain tissue has permittivity magnitudes as high as or greater than 10^8 (100,000,000) times the permittivity of free space (8.854*10^−12 farad per meter), and as such, minimal local perturbations of the relative magnitude can lead to significant displacement current generation. As the frequency of the electric field increases, the relative permittivity decreases by orders of magnitude, dropping to magnitudes of approximately 10^3 times the permittivity of free space (8.854*10^−12 farad per meter) for electric field frequencies of approximately 100,000 Hz. Additionally, by not being constrained to higher electric field frequencies, the method according to the present disclosure is an advantageous method for stimulating biological tissue due to lowered penetration depth limitations and thus lowered field strength requirements. Additionally, because displacement currents are generated in the area of the permittivity change, focusing can be accomplished via the ultrasound alone. For example, to generate capacitive currents via a permittivity perturbation relative to an applied electric field as described above, broad DC or a low frequency electric source field well below the cellular stimulation threshold is applied to a brain region but stimulation effects are locally focused in a smaller region by altering the tissue permittivity in the focused region of a mechanical field generated by a mechanical source such as an ultrasound source. This could be done noninvasively with the electrodes and the ultrasound device both placed on the scalp surface such that the fields penetrate the tissue surrounding the brain region and intersect in the targeted brain location, or with one or both of the electrodes and/or the ultrasound device implanted below the scalp surface (in the brain or any of the surrounding tissue) such that the fields intersect in the targeted region.

A displacement current is generated by the modification of the permittivity in the presence of the sub threshold electric field and provides a stimulatory signal. In addition to the main permittivity change that occurs in the tissues, which is responsible for stimulation (i.e., the generation of the altered currents for stimulation), a conductivity change could also occur in the tissue, which secondarily alters the ohmic component of the currents. In a further embodiment, the displacement current generation and altered ohmic current components may combine for stimulation. Generally, tissue conductivities vary slightly as a function of the applied electric field frequency over the DC to 100,000 Hz frequency range, but not to the same degree as the permittivities, and increase with the increasing frequency of the applied electric field. Additionally in biological tissues, unlike other materials, the conductivity and permittivity do not show a simple one-to-one relationship as a function of the applied electric field frequency. The permittivity ranges are as discussed above.

Although the process described may be accomplished at any frequency of the applied electric field, the method in an exemplary embodiment is applied with lower frequency applied electric fields due to the fact the permittivity magnitudes of tissues, as high as or greater than 10^8 times the permittivity of free space, and the electric field penetration depths are highest for low frequency applied electric fields. Higher frequency applied electric fields may be less desirable as they will require greater radiation power to penetrate the tissue and/or a more pronounced mechanical source for permittivity alteration to achieve the same relative tissue permittivity change, i.e., at higher applied electric field frequencies the permittivity of the tissue is lower and as such would need a greater overall perturbation to have the same overall change in permittivity of a tissue as at a lower frequency. Applied electric field frequencies in the range of DC to approximately 100,000 Hz frequencies are advantageous due to the high tissue permittivity in this frequency band and the high penetration depth for biological tissues at these frequencies. In this band, tissues are within the so called ‘alpha dispersion band’ where relative tissue permittivity magnitudes are maximally elevated (i.e., as high as or greater than 10^8 times the permittivity of free space). Frequencies above approximately 100,000 to 1,000,000 Hz for the applied electric fields are still applicable for the method described in generating displacement currents for the stimulation of biologic cells and tissue, however, both the tissue permittivity and penetration depth are limited for biological tissues in this band compared to the previous band but displacement currents of sufficient magnitude can still be generated for some applications. In this range, the magnitude of the applied electric field will likely need to be increased, or the method used to alter the permittivity relative to the applied electric field increased to bring about a greater permittivity change, relative to the tissue's permittivity magnitude for the applied electric field frequency. Additionally, due to potential safety concerns for some applications, it may be necessary to limit the time of application of the fields or to pulse the fields, as opposed to the continuous application that is possible in the prior band. For tissues or applications where the safety concerns preclude the technique in deeper tissues, the technique could still be applied in more superficial applications in a noninvasive manner or via an invasive method. Higher frequency applied electric fields, above 1,000,000 to 100,000,000 Hz, could be used in generating displacement currents for the stimulation of biologic cells and tissue. However, this would require a more sufficient permittivity alteration or electromagnetic radiation, and as such is less than ideal in terms of safety than the earlier bands. For frequencies of the applied electric field above 100,000,000 Hz, biologic cell and tissue stimulation may still be possible, but may be limited for specialized applications that require less significant displacement currents.

The focus of the electric and mechanical fields to generate an altered current according to the present disclosure may be directed to various structures within the brain or nervous system including but not limited to dorsal lateral prefrontal cortex, any component of the basal ganglia, nucleus accumbens, gastric nuclei, brainstem, thalamus, inferior colliculus, superior colliculus, periaqueductal gray, primary motor cortex, supplementary motor cortex, occipital lobe, Brodmann areas 1-48, primary sensory cortex, primary visual cortex, primary auditory cortex, amygdala, hippocampus, cochlea, cranial nerves, cerebellum, frontal lobe, occipital lobe, temporal lobe, parietal lobe, sub-cortical structures, spinal cord, nerve roots, sensory organs, and peripheral nerves.

The focused tissue may be selected such that a wide variety of pathologies may be treated. Such pathologies that may be treated include but are not limited to Multiple Sclerosis, Amyotrophic Lateral Sclerosis, Alzheimer's Disease, Dystonia, Tics, Spinal Cord Injury, Traumatic Brain Injury, Drug Craving, Food Craving, Alcohol Craving, Nicotine Craving, Stuttering, Tinnitus, Spasticity, Parkinson's Disease, Parkinsonianism, Obsessions, Depression, Schizophrenia, Bipolar Disorder, Acute Mania, Catonia, Post-Traumatic Stress Disorder, Autism, Chronic Pain Syndrome, Phantom Limb Pain, Epilepsy, Stroke, Auditory Hallucinations, Movement Disorders, Neurodegenerative Disorders, Pain Disorders, Metabolic Disorders, Addictive Disorders, Psychiatric Disorders, Traumatic Nerve Injury, and Sensory Disorders. Furthermore, electric and mechanical fields to generate an altered current may be focused on specific brain or neural structures to enact procedures including sensory augmentation, sensory alteration, anesthesia induction and maintenance, brain mapping, epileptic mapping, neural atrophy reduction, neuroprosthetic interaction or control with nervous system, stroke and traumatic injury neurorehabilitation, bladder control, assisting breathing, cardiac pacing, muscle stimulation, and treatment of pain syndromes, such as those caused by migraine, neuropathies, and low-back pain; or internal visceral diseases, such as chronic pancreatitis or cancer. The methods herein could be expanded to any form of arthritis, impingement disorders, overuse injuries, entrapment disorders, and/or any muscle, skeletal, or connective tissue disorder which leads to chronic pain, central sensitization of the pain signals, and/or an inflammatory response.

In the focused region of tissue to which the mechanical fields and electrical fields are delivered, the excitability of individual neurons can be heightened to the point that the neurons can be stimulated by the combined fields, or be affected such as to cause or amplify the alteration of the neural excitability caused by the altered currents, either through an increase or decrease in the excitability of the neurons. This alteration of neural excitability can last past the duration of stimulation and thus be used as a basis to provide lasting treatment. Additionally, the combined fields can be provided in multiple, but separate sessions to have a summed, or carry-over effect, on the excitability of the cells and tissue. The combined fields can be provided prior to another form of stimulation, to prime the tissue making it more or less susceptible to alternate, follow-up forms of stimulation. Furthermore, the combined fields can be provided after an alternate form of stimulation, where the alternate form of stimulation is used to prime the tissue to make it more or less susceptible to the form of stimulation disclosed herein. Furthermore, the combined fields could be applied for a chronic period of time.

FIG. 2 illustrates a set up 30 to perform a method for generating an altered current with a newly generated displacement current 32 for stimulation in biologic tissue 34 through the combined effects of an electric field 36 and a mechanical field 38. A tissue or composite of tissues 34 is placed adjacent to the anode and cathode of an electric source 40 which generates an electric field 36. The electric field 36 is combined with a mechanical, e.g., ultrasound field 38 which can be focused on the tissue 34 and generated via an ultrasound transducer 42. In a sub-region of tissue 44 where the mechanical field 38 is focused and intersects with the electric field 36, a displacement current 32 is generated. By vibrating and/or mechanically perturbing the sub-region of tissue 44, the permittivity of the tissue 44 can be altered relative to the applied electric field 36 to generate a displacement current 32 in addition to the current that would be present due to the source electric field 36 and altered due to conductivity changes in the tissue caused by the mechanical perturbation.

By providing the mechanical field 38 to the sub region of tissue 44, the permittivity can be altered within the electric field 36 by either new elements of the sub region of tissue 44 vibrating in and out of the electric field such that the continuum permittivity of the tissue is changed relative to the electric field 36, or that the bulk properties of the sub region of tissue 44 and the permittivity, or tissue capacitance, change due to the mechanical perturbation. An example of altering the permittivity within the electric field can occur when a cell membrane and extra-cellular fluid, both of different permittivities, are altered in position relative to the electric field by the mechanical field. This movement of tissues of different permittivity relative to the electric field will generate a new displacement current. The tissues could have permittivity values as high as or greater than 10^8 times the permittivity of free space, differ by orders of magnitude, and/or have anisotropic properties such that the tissue itself demonstrates a different permittivity magnitude depending on the relative direction of the applied electric field. An example of altering permittivity of the bulk tissue occurs where the relative permittivity constant of the bulk tissue is directly altered by mechanical perturbation in the presence of an electric field. The mechanical source, i.e., ultrasound source may be placed at any location relative to the electrode locations, i.e., within or outside the same location as the electrodes, as long as components of the electric field and mechanical field are in the same region.

Tissue permittivities can be altered relative to the applied electric fields via a number of methods. Mechanical techniques can be used to either alter the bulk tissue permittivity relative to an applied electric field or move tissue components of differing permittivities relative to an applied electric field. There are no specific limitations to the frequency of the mechanical field that is applied as previously discussed, however, exemplary frequencies range from the sub kHZ to 1000s of MHz. A second electromagnetic field could be applied to the tissue, at a different frequency than the initial frequency of the applied electromagnetic field, such that it alters the tissue permittivity at the frequency dependent point of the initially applied electric field. An optical signal could also be focused on the tissues to alter the permittivity of the tissue relative to an applied electric field. A chemical agent or thermal field could also be applied to the tissues to alter the permittivity of the tissue relative to an applied electric field. These methods could also be used in combination to alter the tissue permittivity relative to an applied electric field via invasive or noninvasive methods.

For example, FIG. 3 shows a set up 50 for generating an altered current with a newly generated displacement current 52 through the combined effects of an electric field 54 and a chemical agent 56. A tissue or composite of tissues 58 is placed within an electric source 60 which generates an electric field 54 and combined with chemical source 62 which releases a chemical agent 56 that can be focused on the tissue 58. In the area that the chemical agent 56 is released in the tissue 64, the electric field 54 transects the sub region of tissue 64, and the chemical agent 56 reacts with the sub region of tissue 64 to alter the tissue's relative permittivity relative to the applied electric field 54. This generates a displacement current 52 in addition to the current that would be present due to the source electric field 54. The chemical agent 56 may be any agent which can react with the tissue or cellular components of the tissue 64 to alter its permittivity relative to the electric field 54. This may be by a thermoreactive process to raise or lower the tissue 64 temperature or through a chemical reaction which alters the distribution of ions in the cellular and extra-cellular media, for instance, along ionic double layers at cell walls in the tissue 64. Similarly, the conformation of proteins and other charged components within the tissue 64 could be altered such that the permittivity of the tissue is altered relative to the low frequency electric field 54. The agent could also be any agent that adapts the permanent dipole moments of any molecules or compounds in the tissue 64, temporarily or permanently relative to the low frequency electric field 54. The chemical reaction driven by the chemical agent 56 must work rapidly enough such that the permittivity of the tissue is quickly altered in the presence of the electric field 54 in order to generate the displacement current 52. The reaction may also be such as to fluctuate the permittivity, such that as the permittivity continues to change displacement currents continue to be generated. In addition to the main permittivity change that occurs in the tissues, a conductivity change could also occur in the tissue, which secondarily alters the ohmic component of the currents. A biological agent may be used in place of, or in addition to, the chemical agent 56. This embodiment may have particular application for focused drug delivery where an additional chemical or biological agent is included to assist in therapy of the tissue, or where the altered current could drive an additional electrochemical reaction for therapy. For example, this could be used in areas such as focused gene therapy or focused chemotherapy.

Another example is shown in FIG. 4, which illustrates a set up 70 for applying a method for generating an altered current with a newly generated displacement current 72 through the combined effects of a low frequency electric field 74 and an electromagnetic radiation field 76. A tissue or composite of tissues 78 is placed within a low frequency electric field 74 which is generated by an electric source 80 and combined with radiation source 82 which generates a radiation field 76 that can be focused on the tissue 78. In the area that the radiation field 76 is focused in the tissue 78, the electric field 74 transects the sub component of tissue 84, where the radiation field 76 interacts with the sub component of tissue 84 to alter the tissue's relative permittivity relative to the applied electric field 74, and as such generates a displacement current 72 in addition to the current that would be present due to the source electric field 74 or the radiation source field 76 alone. The electromagnetic radiation field 76 could, for example, interact with the tissue 84 by altering its temperature through ohmic processes, alter the distribution of ions in the cellular and extra-cellular media for instance along ionic double layers along cell walls through the electric forces acting on the ions, or alter the conformation of proteins and other charged components within the tissue through the electric forces such that the permittivity of the tissue is altered relative to the low frequency electric field 74. Furthermore, the electromagnetic field 76, could interact with the tissue 84 by moving components of the tissue via electrorestrictive forces, as would be seen in anisotropic tissues, to alter the continuum permittivity of the tissue relative to the low frequency electric field 74. In addition to the main permittivity change that occurs in the tissues, a conductivity change could also occur in the tissue, which secondarily alters the ohmic component of the currents.

FIG. 5 shows a set up 90 for applying a method for generating an altered current with a newly generated displacement current 92 through the combined effects of an electric field 94 and an optical beam 96. A tissue or composite of tissues 98 is placed within electric field 94 generated by an electric source 100 and combined with optical source 102 which generates optical beam 96 that can be focused on the tissue 98. In the area that the optical beam 96 is focused on the tissue, the electric field 94 transects the sub component of tissue 104, where the optical beam 96 reacts with the tissue to alter the tissue's relative permittivity relative to the applied electric field 94, and as such generates a displacement current 92 in addition to the current that would be present due to the source electric field 94. The optical beam 96 could, for example, interact with the tissue by altering its temperature through photothermal effects and/or particle excitation, alter the distribution of ions in the cellular and extra-cellular media for instance along ionic double layers along cell walls by exciting the movement of ions optically, ionizing the tissue via laser tissue-interactions, or alter the conformation of proteins and other charged components within the tissue such that the permittivity of the tissue is altered relative to the low frequency electric field 94. In addition to the main permittivity change that occurs in the tissues, a conductivity change could also occur in the tissue, which secondarily alters the ohmic component of the currents.

In another embodiment, a thermal source to alter the permittivity of the tissue may be used. In such embodiments, a thermal source such as a heating probe, a cooling probe, or a hybrid probe may be placed external or internal to the tissue to be stimulated. A thermal source may alter the permittivity of the tissue through the direct permittivity dependence of tissue temperature, mechanical expansion of tissues in response to temperature changes, or by mechanical forces that arise due to altered particle and ionic agitation in response to the temperature alteration such that permittivity of the tissue is altered relative to an applied electric field. In addition to the main permittivity change that occurs in the tissues, a conductivity change could also occur in the tissue, which secondarily alters the ohmic component of the currents. This embodiment may be useful for stimulation in the presence of an acute injury to the tissue where the thermal source could be used to additionally assist in the treatment of the tissue injury, for example with a traumatic brain injury or an infarct in any organ such as the heart. The tissue could be cooled or heated at the same time stimulation is provided to reduce the impact of an injury.

In a further embodiment, the method according to the present disclosure is applied in the area of muscular stimulation, where amplified, focused, direction altered, and/or attenuated currents could be used to alter muscular activity via direct stimulation, depolarizing muscular cells, hyperpolarizing muscular cells, modifying membrane potentials, and/or increasing or decreasing the excitability of the muscle cells. This alteration of excitability or firing patterns can last past the duration of stimulation and thus be used as a basis to provide lasting treatment. Additionally, the stimulation can be provided in multiple, but separate sessions to have a summed, or carry-over effect, on the excitability of cells and tissue. Additionally, the stimulation could be provided to prime the tissue by adjusting the muscle cell excitability to make it more or less susceptible to alternate follow up forms of stimulation. The stimulation could be used after another form of stimulation was used to prime the tissue. Furthermore, the stimulation could be applied for a chronic period of time. This embodiment may be useful for altering or assisting cardiac pacing or function, assisted breathing, muscle stimulation for rehabilitation, muscle stimulation in the presence of nerve or spinal cord injury to prevent atrophy or assist in movement, or as substitution for physical exercise.

In yet another embodiment, the method according to the present disclosure can be applied the area of physical therapy, where amplified, focused, direction altered, and/or attenuated currents could be used to stimulate blood flow, increase or alter neuromuscular response, limit inflammation, speed the break down of scar tissue, and speed rehabilitation by applying the focus of the current generation to the effected region in need of physical therapy. It is envisioned that the method according to the present disclosure may have a wide variety in the area of physical therapy including the treatment or rehabilitation of traumatic injuries, sports injuries, surgical rehabilitation, occupational therapy, and assisted rehabilitation following neural or muscular injury. For instance, following an injury to a joint or muscle, there is often increased inflammation and scar tissue in the region and decreased neural and muscular response. Typically, ultrasound is provided to the affected region to increase blood flow to the region and increase the metabolic re-absorption of the scar tissue while electrical stimulation is provided separately to the nerves and muscles; however, by providing them together, a person could receive the benefit of each individual effect, but additionally amplified stimulatory and metabolic effects through the altered currents. The other methods for generating altered currents discussed within could also be used to assist in physical therapy via the displacement currents that are generated.

Furthermore, the method according to the present disclosure may be applied to the area of cellular metabolism, where currents could be used to interact with electrically receptive cells or charged membranes to alter the tissue or cellular dynamics. It is envisioned that this embodiment could provide treatment for various diseases where electrically receptive cells respond to the newly generated displacement currents and altered current distribution.

Furthermore, the method according to the present disclosure may be applied to the area of gene therapy. Amplified, focused, direction altered, and/or attenuated currents could be used to interact with electrically receptive cells or receptors within the cell to influence protein transcription processes and alter the genetic content of the cells. The altered current densities in the tissue can interact with the tissue to stimulate this altered gene regulation. Additionally, the displacement currents generated by the method could further be used to assist in drug delivery and/or gene therapy through the altered current influence on the delivery of agents.

Furthermore, the method according to the present disclosure may be applied to the area of tissue growth. Combined energies could be used to interact with cells or receptors within the cell to influence cell growth (and/or tissue(s)) and/or alter cellular (and/or tissue(s)) processes and/or structures. Stimulation can be used to increase and or slow cell and/or tissue growth and/or affect tumors, such as through ablation methods whereby energies can be used to ablate tissues or with methods whereby combined energies can create tumor treating fields. For instance, with electromechanical stimulation, altered electromagnetic fields generated via electromechanical coupling can affect the tissues, while in certain embodiments the mechanical fields could also have a further therapeutic effect.

The methods and devices of this disclosure involve providing a first type of energy to a region of tissue, in which the first type is provided in an amount that inhibits cellular function within the region of tissue, and providing a second type of energy to the region of tissue, in which the second type is provided in an amount that facilitates cellular function within the region of tissue, wherein the combined effect stimulates cellular function within the tissue. In certain embodiments, the stimulatory effect is facilitatory to the cellular function within the tissue (and in certain embodiments, the stimulatory effect can have a greater facilitatory effect than that of the second type of energy alone). In other embodiments, the stimulatory effect is inhibitory to the cellular function within the tissue (and in certain embodiments, the stimulatory effect can have a greater inhibitory effect than that of the first type of energy alone). For example, providing one energy type with specific parameters inhibits certain electrical, thermal, mechanical, optical, and/or chemical functions of a cell (such as in size and/or timing), yet the application of a second energy type with specific parameters facilitates certain electrical, thermal, mechanical, optical, and/or chemical functions of a cell, but the combined application of the energies leads to an inhibitory effect(s) greater than the first energy applied alone or a facilitatory effect(s) greater than the second energy type applied alone. The stimulation can be applied to affect multiple functions of the cell, whereby the combined energies could have multiple facilitatory and/or inhibitory effects on the cell (and/or the individual energies can have their own independent effects). Furthermore the methods described herein could be applied to extend (or decrease) the duration of stimulatory effect of one (or both) of the energy types on cellular function, whereby the combined effects of the two energies lead to an extended duration of effect of one (or both) of the stimulatory energies.

The direction of cellular effect (inhibitory or facilitatory) can be controlled by any of the energy types applied, depending on the energy source parameters and the targeted tissue. For example with a transcranial DC electrical energy source applied in conjunction with a transcranial ultrasound energy source (such as might be used for imaging or stimulation), the DC electrical energy source characteristics could be used to determine the direction of typical cellular response during transcranial application (i.e., the polarity of the electrical field); for example one could apply a DC electrical field in conjunction with any typical ultrasound field transcranially to a neural target in the brain, where the DC electrical field and the ultrasound field could be provided in either a facilitatory or inhibitory manner, but the DC electric field is used determine the direction of stimulatory effect, such as could be done with a tDCS stimulation device in conjunction with an ultrasound imaging system, where the polarity of the tDCS fields are used for controlling the direction of combined effect. For instance if one provided a DC electrical field (such as what could be done transcranially from an anodal scalp electrode (with approximately 2 mA/25 cm^2 current density amplitude, as reported at the scalp source)) focused on the visual cortex while simultaneously providing an ultrasound stimulation with inhibitory properties to the same area (such as could be done with an ultrasound source providing a typical transcranial imaging signal of approximately a 2.4 MHz center frequency (where the center frequency refers to the NEMA center frequency, calculated in accordance with NEMA UD2 (NEMA Acoustic Output Measurement Standard) defined as Fc=(f1+f2)/2 where f1 and f2 are the frequencies at which the transmitted acoustic pressure spectrum is 71% (−3 dB) of its maximum value), with a Max Ispta.3 of ˜0.2 W/cm^2 (the derated (at 0.3 dB/cmMHz) Spatial-Peak Temporal-Average intensity (mW/cm^2)), the Max Isppa.3 of ˜33 W/cm^2 (the derated (at 0.3 dB/cmMHz) Spatial-Peak Pulse-Average intensity (W/cm2)), and a Max Imax.3 of ˜46 W/cm^2 (the derated (at 0.3 dB/cmMHz) maximum half-cycle intensity value acquired at the depth where Pii.3 is maximized (W/cm^2))) the overall effect on the neural target would be facilitatory (although the techniques provided individually would elicit facilitatory (tDCS) and inhibitory (ultrasound) effects). However, by altering the relative position of the DC source (such as by placing it inside the brain) and both lowering its strength and reversing its polarity, such that it was a cathodal source (for further examples describing anodal vs cathodal effects see (Wagner, Valero-Cabre and Pascual-Leone, Noninvasive Human Brain Stimulation, Annu Rev Biomed Eng, 2007) or its references (Bindman, Lippold and Redfearn, The Action of Brief Polarizing Currents on the Cerebral Cortex of the Rat (1) During Current Flow and (2) in the Production of Long-Lasting after-Effects, J Physiol, 172, (369-82, 1964), (Bindman L J, Long-lasting changes in the level of the electrical activity of the cerebral cortex produced by polarizing currents, Nature 196, (584-85, 1962), (Purpura and McMurtry, Intracellular Activities and Evoked Potential Changes During Polarization of Motor Cortex, J Neurophysiol, 28, (166-85, 1965), and (Terzuolo and Bullock, Measurement of Imposed Voltage Gradient Adequate to Modulate Neuronal Firing, Proc Natl Acad Sci USA, 42, (9), 687-694, 1956)), the relative electric field effect on the visual cortex would be the same as having used the anodal stimulation on the scalp surface (and thus the combined effect would be the same, but driven by the cathodal driven electric field (but where the relative field effects are the same)). However, by flipping the polarity of the electrical source field in either example the combined effects would no longer be facilitatory, but inhibitory. (Although the general convention in transcranial brain stimulation methods is reported using the energy source positions on the scalp, one ultimately determines the direction of stimulation of the combined fields by accounting for the energy fields at the site of action (i.e., the stimulatory field(s) direction and timing at the site of the stimulated cell(s)) and thus while providing specific examples herein of transcranial applications (where we generally follow convention of reporting the effects relative from the scalp application site), the amplitude, source location, timing, and/or vector orientation of the energy fields (and direction of neural effect (i.e., inhibitory or facilitatory) can be modified by changing the location and/or characteristics of the stimulation energy source(s) (and their applied energies)).

And while above we provide an example for combined electrical and mechanical stimulation where the DC electric field is used to control the direction of effect (i.e., inhibitor/facilitatory), the relative interactions between the two energy types can be used to determine and control the stimulatory effect direction. For instance, one could also alter the ultrasound parameters instead of the electrical source characteristics to control the direction of neural effect (such as one could provide a DC electric field, but alter the direction of neural response (i.e., inhibitor/facilitatory) through the pulse shape, pulse frequency, spectral components, and/or relative direction of the mechanical fields provided by the ultrasound source (relative to the DC field)). For example, one could provide an electrical field, such as through a DC current source which was inhibitory to the neural targets (such as a cathodal application of a low intensity current to the cortex from a scalp electrode overlying the entire scalp (and thus cortex) with an indifferent electrode placed below the mouth of the individual being stimulated) but also provide a pulsed transcranial ultrasonic field to a focused target in the presence of the broad field (for example with a 0.7 MHz field, pulsed on and off (for short pulse durations, for example for a period shorter than the refractory period of the targeted cells, or for instance at a 65 microsecond duration, or just for one quarter of a wave-cycle) at a frequency greater than 20 Hz) to the same brain area. The coupling of the fields can lead to an amplified electrical current in the tissue (at the frequency in which the ultrasonic field is turned on and off), which can ultimately have a facilitatory effect on the neural targets, such as for example those in the motor cortex (one can provide the electric field at an intensity where its effects alone are negligible in the targeted region, or at a level where the combined effects are greater than that of its individual effects). As another example, one could provide the same electrical field, but alter the mechanical field such that it is pulsed on and off at a 1 Hz frequency, this in turn would lead to an overall inhibitory effect on the neural targets.

Furthermore, one could vary both of the electrical and mechanical fields (e.g., the relative timing, phase, frequency (pulse or spectral power of individual pulses), shape, dynamics, direction, and/or amplitude of the applied energy fields), such as with a control device and/or methodology whereby the field parameters are controlled and/or tuned to the desired effect (facilitatory or inhibitory (and magnitude of effect, timing of effect, duration of effect)) based on the combined field analysis relative to the neural response. These parameters could be altered continuously, whereby combined effects (that when provided individually could have contrasting effects) provide stimulatory effects that are greater than either of the individual modality applied individually.

Ultimately, one could calculate, optimize, tune, or guide the combined energy field effects (such as those driven by an electric field source and a mechanical field source) with any computational method such as those explained co-owned and co-pending U.S. patent application Ser. No. 13/216,282 the content of which is incorporated by reference herein in its entirety (and/or integrated with imaging data and/or tissue property data and/or feedback information, such as those explained co-owned and co-pending U.S. patent application Ser. No. 13/162,047 the content of which is incorporated by reference herein in its entirety).

In another potential embodiment these methods could be implemented to effectively provide ‘noise’ to the cellular system that is targeted, or provide continuously alternating inhibitory and facilitatory signals to alter normal cellular function (either with combined stimulatory methods (i.e., multiple energy types) and/or with individual energy types).

All of the methods and processes discussed in this document could be implemented with any form of stimulation, including but not limited to electromagnetic, mechanical, optical, thermal, electrical, magnetic, and/or combined methods (and/or methods which alter tissue impedances relative to electrical sources to generate altered stimulation currents, for example with electromagnetic, chemical, mechanical, optical, thermal, electrical, magnetic, and/or combined sources). Typically, the two energy components would be simultaneously applied; but, using one energy type to prime the tissue for one or more energy types is also possible, either sequentially applying the energies or with a period of time in between the second energy application.

Furthermore the methods demonstrated herein could be extended to work with more than just two energy types, and the direction of effect (inhibitory or facilitatory) determined via the combined energy analysis working through the different permutations as described above. As in the other methods with two energy types, the dynamics of the energy source(s) could be altered in a manner to control direction (e.g., inhibitory, facilitory) of the combined effect on cellular function. As in the other methods with two energy types, the direction of the neural effect with more than two energy types can be determined by the methods outlined herein in conjunction with co-pending and co-owned U.S. patent application Ser. No. 13/216,282.

INCORPORATION BY REFERENCE

References and citations to other documents, such as patents, patent applications, patent publications, journals, books, papers, web contents, have been made throughout this disclosure. All such documents are hereby incorporated herein by reference in their entirety for all purposes.

EQUIVALENTS

The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting on the invention described herein.

EXAMPLES Example 1 Combination of Inhibitory and Facilitatory Amounts of Energy

Electrophysiology protocols focused on comparing the combined local visual evoked potentials (VEP) recorded from a 23 contact electrode, implanted in area 17 (i.e., primary visual cortices, V1) of anaesthetized adult cats (n=6) during and immediately following transcranial stimulations applied to the V1. Application of a mechanical field (TUS (2.4 MHz/0.2 W/cm2)), an electrical field (tDCS (2 mA DC/9 cm2, anodal)), a combination of a mechanical field and an electrical field (ESSstim (2 mA DC/9 cm2, 2.4 MHz/0.2 W/cm2)), and a SHAM (inactive transducer) were evaluated (i.e., stimulations completed transcranially from an anodal scalp electrode (with a ˜2 mA/9 cm^2 current density amplitude, as reported at the scalp source) and a ultrasound scalp source (a 2.4 MHz center frequency (where the center frequency refers to the NEMA center frequency, calculated in accordance with NEMA UD2 (NEMA Acoustic Output Measurement Standard) defined as Fc=(f1+f2)/2 where f1 and f2 are the frequencies at which the transmitted acoustic pressure spectrum is 71% (−3 dB) of its maximum value), with a Max Ispta.3 of ˜0.2 W/cm^2 (the derated (at 0.3 dB/cmMHz) Spatial-Peak Temporal-Average intensity (mW/cm^2)), the Max Isppa.3 of ˜33 W/cm^2 (the derated (at 0.3 dB/cmMHz) Spatial-Peak Pulse-Average intensity (W/cm2)), and a Max Imax.3 of ˜46 W/cm^2 (the derated (at 0.3 dB/cmMHz) maximum half-cycle intensity value acquired at the depth where Pii.3 is maximized (W/cm^2))). Dosing was applied for 5 min periods. Although anesthesia and low stimulation doses were used to minimize the offline/carryover effects of stimulation, each application of stimulation was followed by a variable washout period, where the real-time VEP response was monitored and allowed to return to the range of the pre-stimulation VEPs (15 min minimum, assessed in 5 min blocks).

A 3-way ANOVA (Dependent: Area Under VEP Curve (i.e., measure of cortical excitability); Independent: Stimulation Type, Time, and Cat) demonstrated a highly significant effect of stimulation type (F3,14699=73.97, p≈0), time (analyzed in 5 minute epochs (i.e., online, 0-5, 5-10, and 1045 mins)) (F3,14699=90.68, p≈0), and cat (F5,14699=40.31, p≈0). A subsequent comparison of the means (with a least squares difference (LSD) correction, with p set as p<0.05), demonstrated a significant difference between all of the techniques during their online periods. It was observed that application of the mechanical field alone had a suppressive effect on cellular function within the region of tissue, and that application of the electric field had a facilitatory effect on cellular function within the region of tissue. See FIG. 6 panels A-C. It was observed that combining the mechanical field and the electrical field at the same dosing as they were applied individually facilitated cellular function within the tissue, and that the stimulation of cellular function was approximately 4 times greater than the stimulation of cellular function observed from the electrical field alone. See FIG. 6 panels A-C.

A secondary analysis of the techniques as a function of stimulation type, time, and contact depth (F367,14388=3.24, p≈0) accounting for cat to cat variability was undertaken where a multiple comparison of means, with an LSD correction (p<0.05), demonstrated the online effects of the combination of the mechanical field and the electrical field to be significant throughout every contact (from surface to deeper contacts) and the electrical field to only be significant at the cortical surface. The mechanical field alone had an insignificant effect at any individual contact site but was consistently suppressive (See FIG. 6 panels A-C).

Finally, in a sub cat group (n=3 complete), randomized transcranial stimulations to the V1, the frontal eye field (A6), and the posterior middle suprasylvian sulcus (PMS) areas have been made with comparisons being made among a combination of a mechanical field and electrical field, an electrical field alone, a mechanical field alone, and a SHAM field (i.e., inactive transducers). In these animals, the results demonstrated V1 and PMS stimulation effects similar to above (with the V1 stimulations demonstrating a slightly larger effect than PMS, although not greatly different); and in the deepest target (A6), the combination of the mechanical field and the electrical field was the only technique to demonstrate any consistent effect in neural activity (approximately +5.8% change in the VEP magnitude).

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US283057831 Jan 195715 Apr 1958Mark E DegroffElectro-sonic apparatus
US283867229 Jun 195410 Jun 1958Physical Medicine Products CoElectro-therapy generator
US373575623 Jun 197129 May 1973Medco Products Co IncDuplex ultrasound generator and combined electrical muscle stimulator
US38227087 Dec 19729 Jul 1974Clinical Technology CorpElectrical spinal cord stimulating device and method for management of pain
US430540229 Jun 197915 Dec 1981Katims Jefferson JMethod for transcutaneous electrical stimulation
US450386315 Sep 198112 Mar 1985Katims Jefferson JMethod and apparatus for transcutaneous electrical stimulation
US453578523 Sep 198220 Aug 1985Minnesota Mining And Manufacturing Co.Method and apparatus for determining the viability and survival of sensori-neutral elements within the inner ear
US461159614 Oct 198016 Sep 1986Purdue Research FoundationSensory prostheses
US464163325 Apr 198510 Feb 1987Delgado Jose M RElectronic system for the activation, inhibition and/or modification of the development and functioning of cells, organs and organisms of living beings
US467295130 Dec 198516 Jun 1987Bio-Electric, Inc.Method and apparatus for treatment of biological tissue
US472353611 Sep 19859 Feb 1988Rauscher Elizabeth AExternal magnetic field impulse pacemaker non-invasive method and apparatus for modulating brain through an external magnetic field to pace the heart and reduce pain
US475937726 Nov 198626 Jul 1988Regents Of The University Of MinnesotaApparatus and method for mechanical stimulation of nerves
US480563620 Nov 198721 Feb 1989The University Of MichiganSystem for controlling muscle response
US488952613 Nov 198726 Dec 1989Magtech Laboratories, Inc.Non-invasive method and apparatus for modulating brain signals through an external magnetic or electric field to reduce pain
US492343727 Sep 19888 May 1990Gordon Robert TProcess for applying a localized magnetic or electric field
US501469930 Nov 198914 May 1991Trustees Of The University Of PennsylvaniaElectromagnetic method and apparatus for healing living tissue
US506123425 Sep 198929 Oct 1991Corteks, Inc.Magnetic neural stimulator for neurophysiology
US511385925 Jun 199019 May 1992Medtronic, Inc.Acoustic body bus medical device communication system
US527769413 Feb 199211 Jan 1994Implex GmbhElectromechanical transducer for implantable hearing aids
US530009314 Sep 19925 Apr 1994Telectronics Pacing Systems, Inc.Apparatus and method for measuring, formatting and transmitting combined intracardiac impedance data and electrograms
US55451245 May 199413 Aug 1996Siemens AktiengesellschaftMethod for alleviating the sensation of pain
US556959121 Jul 199429 Oct 1996University College Of Wales AberystwythAnalytical or monitoring apparatus and method
US557576127 Jul 199419 Nov 1996Hajianpour; Mohammed-AliMassage device applying variable-frequency vibration in a variable pulse sequence
US558258626 Sep 199310 Dec 1996Tachibana; KatsuroDrug administration and humor sampling unit and an apparatus therefor
US571392225 Apr 19963 Feb 1998Medtronic, Inc.Techniques for adjusting the locus of excitation of neural tissue in the spinal cord or brain
US57761704 Feb 19947 Jul 1998Macdonald; Alexander John RanaldElectrotherapeutic apparatus
US57761717 Jun 19957 Jul 1998Case Western Reserve UniversityFunctional neuromuscular stimulation system
US589388330 Apr 199713 Apr 1999Medtronic, Inc.Portable stimulation screening device for screening therapeutic effect of electrical stimulation on a patient user during normal activities of the patient user
US592507010 Mar 199720 Jul 1999Medtronic, Inc.Techniques for adjusting the locus of excitation of electrically excitable tissue
US59750851 May 19972 Nov 1999Medtronic, Inc.Method of treating schizophrenia by brain stimulation and drug infusion
US603523613 Jul 19987 Mar 2000Bionergy Therapeutics, Inc.Methods and apparatus for electrical microcurrent stimulation therapy
US608174417 Jul 199827 Jun 2000Loos; Hendricus G.Electric fringe field generator for manipulating nervous systems
US609199215 Dec 199718 Jul 2000Medtronic, Inc.Method and apparatus for electrical stimulation of the gastrointestinal tract
US609459825 Apr 199625 Jul 2000Medtronics, Inc.Method of treating movement disorders by brain stimulation and drug infusion
US610287516 Jan 199715 Aug 2000Jones; Rick E.Apparatus for combined application of massage, accupressure and biomagnetic therapy
US61285371 May 19973 Oct 2000Medtronic, IncTechniques for treating anxiety by brain stimulation and drug infusion
US616104826 Jun 199712 Dec 2000Radionics, Inc.Method and system for neural tissue modification
US616940327 Apr 19992 Jan 2001Siemens AktiengesellschaftMethod and MR device for simulating electrical simulations in a subject by MR stimulation
US620535626 Apr 199920 Mar 2001Robert R. HolcombElectronic apparatus and method for treating human pain through application of an electrical stimulus in combination with application of a magnetic field
US623160426 Feb 199915 May 2001Med-El Elektromedizinische Gerate Ges.M.B.HApparatus and method for combined acoustic mechanical and electrical auditory stimulation
US62757357 Jul 199914 Aug 2001Bionergy Therapeutics, Inc.Methods and apparatus for electrical microcurrent stimulation therapy
US627573723 Jun 199914 Aug 2001Advanced Bionics CorporationTranscutaneous transmission pouch
US633047628 Nov 200011 Dec 2001Impulse Dynamics N.V.Electrical muscle controller using a non-excitatory electric field
US63756669 Dec 199923 Apr 2002Hans Alois MischeMethods and devices for treatment of neurological disorders
US639099525 Jun 199921 May 2002Healthtronics Surgical Services, Inc.Method for using acoustic shock waves in the treatment of medical conditions
US639332517 Apr 200021 May 2002Advanced Bionics CorporationDirectional programming for implantable electrode arrays
US640821116 Jun 200018 Jun 2002Newcare Products, LlcMicrocurrent therapy device
US64320709 May 200013 Aug 2002Exogen, Inc.Method and apparatus for ultrasonic treatment of reflex sympathetic dystrophy
US646332810 Jan 20008 Oct 2002Michael Sasha JohnAdaptive brain stimulation method and system
US646827411 Oct 200022 Oct 2002Arthrocare CorporationSystems and methods for treating spinal pain
US649103931 Mar 200010 Dec 2002Innercool Therapies, Inc.Medical procedure
US653576721 Aug 200118 Mar 2003James W. KronbergApparatus and method for bioelectric stimulation, healing acceleration and pain relief
US653644017 Oct 200025 Mar 2003Sony CorporationMethod and system for generating sensory data onto the human neural cortex
US654629012 Apr 20008 Apr 2003Roamitron Holding S.A.Method and apparatus for electromedical therapy
US656770213 Oct 200020 May 2003The Board Of Trustees Of The Leland Stanford Junior UniversityEliciting analgesia by transcranial electrical stimulation
US658435717 Oct 200024 Jun 2003Sony CorporationMethod and system for forming an acoustic signal from neural timing difference data
US659113831 Aug 20008 Jul 2003Neuropace, Inc.Low frequency neurostimulator for the treatment of neurological disorders
US661508029 Mar 20012 Sep 2003John Duncan UnsworthNeuromuscular electrical stimulation of the foot muscles for prevention of deep vein thrombosis and pulmonary embolism
US665464211 Dec 200025 Nov 2003Medtronic, Inc.Patient interactive neurostimulation system and method
US668113116 Oct 200120 Jan 2004Hitachi, Ltd.Apparatus for measuring bio-magnetic fields
US668572924 Jul 20013 Feb 2004George GonzalezProcess for testing and treating aberrant sensory afferents and motors efferents
US669249028 Sep 199917 Feb 2004Novasys Medical, Inc.Treatment of urinary incontinence and other disorders by application of energy and drugs
US672160325 Jan 200213 Apr 2004Cyberonics, Inc.Nerve stimulation as a treatment for pain
US672933728 Jan 20034 May 2004Sony CorporationMethod and system for generating sensory data onto the human neural cortex
US682451525 Nov 200230 Nov 2004Scimed Life Systems, Inc.Ultrasound-guided ablation catheter and methods of use
US683668510 Jan 200028 Dec 2004William R. FitzNerve stimulation method and apparatus for pain relief
US685800022 Feb 200122 Feb 2005Olga Pavlovna BaryshevaDevice for treating tissues with an electromagnetic field
US686667810 Dec 200215 Mar 2005Interbational Technology CenterPhototherapeutic treatment methods and apparatus
US687109913 Aug 200122 Mar 2005Advanced Bionics CorporationFully implantable microstimulator for spinal cord stimulation as a therapy for chronic pain
US688908520 May 20033 May 2005Sony CorporationMethod and system for forming an acoustic signal from neural timing difference data
US692141315 Aug 200126 Jul 2005Vanderbilt UniversityMethods and devices for optical stimulation of neural tissues
US693458018 Jul 200323 Aug 2005Flint Hills Scientific, L.L.C.Stimulation methodologies and apparatus for control of brain states
US693790629 Jan 200230 Aug 2005Medtronic, Inc.Method and apparatus for detecting static magnetic fields
US694117116 Aug 20016 Sep 2005Advanced Bionics CorporationImplantable stimulator methods for treatment of incontinence and pain
US696464315 Feb 200215 Nov 2005Nugyn, Inc.Devices and methods for treatment of incontinence
US697074413 Aug 200329 Nov 2005Pacesetter, Inc.Bioenergy generator
US697699817 Jan 200320 Dec 2005Massachusetts Institute Of TechnologyMinimally invasive retinal prosthesis
US700279030 Sep 200221 Feb 2006Medtronic, Inc.Capacitor in an implantable medical device
US70033522 May 200321 Feb 2006Advanced Bionics CorporationTreatment of epilepsy by brain stimulation
US70131773 Jul 200214 Mar 2006Advanced Bionics CorporationTreatment of pain by brain stimulation
US705844723 Apr 20036 Jun 2006Medtronic, Inc.Method and system for directing blood flow during a medical procedure
US710494717 Nov 200312 Sep 2006Neuronetics, Inc.Determining stimulation levels for transcranial magnetic stimulation
US712049729 Oct 200210 Oct 2006Metacure NvSmooth muscle controller
US717313028 Sep 20016 Feb 2007The Regents Of The University Of CaliforniaDetection of transmembrane potentials by optical methods
US728386130 Apr 200216 Oct 2007Alexander BystritskyMethods for modifying electrical currents in neuronal circuits
US819740923 Feb 200912 Jun 2012University Of WashingtonUltrasound guided high intensity focused ultrasound treatment of nerves
US8774914 *1 Nov 20138 Jul 2014Highland Instruments, Inc.Systems and methods for stimulating cellular function in tissue
US2007029937027 Aug 200727 Dec 2007Alexander BystritskyMethods for modifying electrical currents in neuronal circuits
US200800398956 Apr 200714 Feb 2008Northstar Neuroscience, Inc.Electromagnetic signal delivery for tissue affected by neuronal dysfunction, degradation, damage, and/or necrosis, and associated systems and methods
US2008004605318 Jun 200721 Feb 2008Wagner Timothy AApparatus and method for stimulation of biological tissue
US2009001859913 Sep 200715 Jan 2009Boston Scientific Scimed, Inc.Cardiac Stimulation Using Leadless Electrode Assemblies
Non-Patent Citations
Reference
1Advanced Development for Defense Science and Technology, Apr. 5, 2010, 93 pages.
2Allen, E.A., et al., Transcranial magnetic stimulation elicits coupled neural and hemodynamic consequences. Science, 2007. 317(5846): p. 1918-1921.
3Aydin-Abidin, S., et al., Effects of repetitive TMS on visually evoked potentials and EEG in the anesthetized cat: dependence on stimulus frequency and train duration. J Physiol, 2006.
4Benabid, A.L., et al., Deep brain stimulation of the corpus luysi (subthalamic nucleus) and other targets in Parkinson's disease. Extension to new indications such as dystonia and epilepsy. J Neurol, 2001. 248 Suppl 3: p. III37-III47.
5Bindman LJ, L.O., Redfearn JW. , Long-lasting changes in the level of the electrical activity of the cerebral cortex produced by polarizing currents. Nature 1962. 196: p. 584-585.
6Bindman, L.J., O.C. Lippold, and J.W. Redfearn, The Action of Brief Polarizing Currents on the Cerebral Cortex of the Rat (1) During Current Flow and (2) in the Production of Long-Lasting after-Effects. J Physiol, 1964. 172: p. 369-382.
7Bostock, H., The strength-duration relationship for excitation of myelinated nerve: computed dependence on membrane parameters. J Physiol, 1983. 341: p. 59-74.
8Boyden, E.S., et al., Millisecond-timescale, genetically targeted optical control of neural activity. Nat Neurosci, 2005. 8 (9): p. 1263-1268.
9Brice, J. and L. McLellan, Suppression of intention tremor by contingent deep-brain stimulation. Lancet, 1980. 1(8180): p. 1221-1222.
10Britten, K.H. and R.J. van Wezel, Electrical microstimulation of cortical area MST biases heading perception in monkeys. Nat Neurosci, 1998. 1(1): p. 59-63.
11Brown, J.A., et al., Motor cortex stimulation for the enhancement of recovery from stroke: a prospective, multicenter safety study. Neurosurgery, 2006. 58(3): p. 464-473.
12Butovas, S. and C. Schwarz, Spatiotemporal effects of microstimulation in rat neocortex: a parametric study using multielectrode recordings. J Neurophysiol, 2003. 90(5): p. 3024-3039.
13Butson CR, McIntyre CC (2005) Tissue and electrode capacitance reduce neural activation volumes during deep brain stimulation. Clin Neurophysiol 116:2490-2500.
14Butson, C.R. and C.C. McIntyre, Role of electrode design on the volume of tissue activated during deep brain stimulation. J Neural Eng, 2006. 3(1): p. 1-8.
15Butson, C.R. and C.C. McIntyre. Deep brain Stimulation of the the subthalamic nucleus: model-based analysis of the effects of electrode capacitance on the volume of activation. In 2nd International IEEE EMBS Conference on Neural Engineerin. 2005. Arlington, VA: IEEE.
16Carbunaru, R. and D.M. Durand, Toroidal coil models for transcutaneous magnetic stimulation of nerves. IEEE Trans Biomed Eng, 2001. 48(4): p. 434-441.
17Chew, W.C. and P.N. Sen, Dielectric enhancement due to an electrochemical double layer: thin double layer approximation. J. Chem. Phys., 1982. 77: p. 4683.
18Chew, W.C., Dielectric enhancement and electrophoresis due to electrochmical double layer: A uniform approximation. J Chem Phys. 80(9): p. 4541-4552.
19Clement, G.T. and K. Hynynen, A non-invasive method for focusing ultrasound through the human skull. Phys Med Biol, 2002. 47(8): p. 1219-1236.
20Clement, G.T., et al., A magnetic resonance imaging-compatible, large-scale array for trans-skull ultrasound surgery and therapy. J Ultrasound Med, 2005. 24(8): p. 1117-1125.
21Clement, G.T., Perspectives in clinical uses of high-intensity focused ultrasound. Ultrasonics, 2004. 42(10): p. 1087-1093.
22Cohen, D. and B.N. Cuffin, Developing a more focal magnetic stimulator. Part 1: some basic principles. Journal of Clinical Neurophysiology, 1991.8: p. 102-111.
23Cohen, L.G., et al., Effects of coil design on delivery of focal magnetic stimulation. Technical considerations. Electroencephalogr Clin Neurophysiol, 1990. 75(4): p. 350-357.
24Cohen, M.R. and W.T. Newsome, What electrical microstimulation has revealed about the neural basis of cognition. Curr Opin Neurobiol, 2004. 14(2): p. 169-177.
25Connor, C.W. and K. Hynynen, Patterns of Thermal Deposition in the Skull During Transcranial Focused Ultrasound Surgery. IEEE Trans Biomed Eng, 2004. 51(10): p. 1693-1706.
26Connor, C.W., G.T. Clement, and K. Hynynen, A unified model for the speed of sound in cranial bone based on genetic algorithm optimization. Phys Med Biol, 2002. 47(22): p. 3925-3944.
27Cramer, S.C., et al., Use of functional MRI to guide decisions in a clinical stroke trial. Stroke, 2005. 36(5): p. e50-e52.
28Deuschl, G., et al., Deep brain stimulation: postoperative issues. Mov Disord, 2006. 21 Suppl 14: p. S219-S237.
29Di Lazzaro, V., et al., The physiological basis of transcranial motor cortex stimulation in conscious humans. Clin Neurophysiol, 2004. 115(2): p. 255-266.
30Diamond, A. and J. Jankovic, The effect of deep brain stimulation on quality of life in movement disorders. J Neurol Neurosurg Psychiatry, 2005. 76(9): p. 1188-1193.
31Diokno, A.C., P.B. Leu, and D.B. Konstandt, A simplified method of implanting a neuromodulator device. J Urol, 2003. 169(4): p. 1466-1469.
32Dissado, L.A., A fractal interpertation of the dielectric response of animal tissues. Phys. Med. Biol., 1990. 35(11): p. 1487-1503.
33Ditterich, J., M.E. Mazurek, and M.N. Shadlen, Microstimulation of visual cortex affects the speed of perceptual decisions. Nat Neurosci, 2003. 6(8): p. 891-898.
34Donald I. McRee, Howard Wachtel, Pulse Microwave Effects on Nerve Vitality, Radiation Research, vol. 91, No. 1 (Jul. 1982).
35Duck, F.A., Medical and non-medical protection standards for ultrasound and infrasound. Prog Biophys Mol Biol, 2007. 93(1-3): p. 176-191.
36Durand, D. and M. Bikson, Suppression and control of epileptiform activity by electrical stimulation: a review. Proceedings of the IEEE, 2001. 89(7): p. 1065-1082.
37Eaton, H., Electric field induced in a spherical volume conductor from arbitrary coils: applications to magnetic stimulation and MEG. Medic Biol Eng Comput, 1992: p. 433-440.
38Esselle, K. and M. Stuchly, Neural stimulation with magnetic fields: analysis of induced electrical fields. IEEE Transactions on Biomedical Engineering, 1992. 39: p. 693-700.
39Fields, J.A., et al., Neuropsychological and quality of life outcomes 12 months after unilateral thalamic stimulation for essential tremor. J Neurol Neurosurg Psychiatry, 2003. 74(3): p. 305-311.
40Fixman, M., Charged macromolecules in external fields. I. The sphere. J Chem Phys, 1980. 72(9): p. 5177-5186.
41Fixman, M., Thin double layer approximation for electrophoresis and dielectric respons. J Chem Phys, 1982. 78(3): p. 1483-1492.
42FralexTherapeutics, Fralex Provides Update on Relief Trial. 2008: Toronto.
43Fregni, F. and A. Pascual-Leone, Technology insight: noninvasive brain stimulation in neurology-perspectives on the therapeutic potential of rTMS and tDCS. Nat Clin Pract Neurol, 2007. 3(7): p. 383-393.
44Fry WJ, W.V., Tucker D, Fry FJ, Physical factors involved in ultrasonically induced changes in living systems: I. Identification of non-temperature effects. J Acoust Soc Am 1950. 22: p. 867-876.
45Fry, E.J., An ultrasonic projector design for a wide range of research applications. Rev Sci Instrum, 1950. 21(11): p. 940-941.
46Fry, W. J., Electrical Stimulation of Brain Localized Without Probes-Theoretical Analysis of a Proposed Method, J Acoust Soc Am 44(4): 919-931. (1968).
47Fry, W. J., Electrical Stimulation of Brain Localized Without Probes—Theoretical Analysis of a Proposed Method, J Acoust Soc Am 44(4): 919-931. (1968).
48Fry, W.J., Use of intense ultrasound in neurological research. Am J Phys Med, 1958. 37(3): p. 143-147.
49Gabriel, C., S. Gabriel, and E. Corthout, the dielectric properties of biological tissues: I. Literature survey. Phys Med Biol, 1996. 41(11): p. 2231-2249.
50Gabriel, S., R.W. Lau, and C. Gabriel, The dielectric properties of biological tissues: II. Measurements in the frequency range 10 Hz to 20 GHz. Phys Med Biol, 1996. 41(11): p. 2251-2269.
51Gabriel, S., R.W. Lau, and C. Gabriel, The dielectric properties of biological tissues: Ill. Parametric models for the dielectric spectrum of tissues. Phys Med Biol, 1996. 41(11): p. 2271-2293.
52Gielen, F. Deep Brain Stimulation: Current Practice and Challenges for the Future. in 1st International IEEE EMBS Conference on Neural Engineering. 2003. Capri Island, Italy: IEEE.
53Graziano, M.S., C.S. Taylor, and T. Moore, Complex movements evoked by microstimulation of precentral cortex. Neuron, 2002. 34(5): p. 841-851.
54Grill, W.M., et al., Temporal excitation properties of paresthesias evoked by thalamic microstimulation. Clin Neurophysiol, 2005. 116(5): p. 1227-1234.
55Grill, W.M., S.E. Norman, and R.V. Bellamkonda, Implanted neural interfaces: biochallenges and engineered solutions. Annu Rev Biomed Eng, 2009. 11: p. 1-24.
56Grosse, C., Permitivity of suspension of charged particles in electolyte solution. J. Chem. Phys., 1987. 91: p. 3073.
57Gusev, V., et al., Imaging With the Ultrasonic Vibration Potential: A Theory for Current Generation. Ultrasound in Med. & Biol., 2005. vol. 31, No. 2, pp. 273-278.
58Haar, G.t., Accoustic Surgery. Physics Today, 2001: p. 29-34.
59Hart FX, Toll RB, Berner NJ, Bennett NH (1996) The low frequency dielectric properties of octopus arm muscle measured in vivo. Phys Med Biol 41:2043-2052.
60Hart, F.X. and W.R. Dunfree, in vivo measurements of low frequency dielectric spectra of a frog skeletal muscle. Phys. Med. Biol., 1993. 38: p. 1099-1112.
61Hatanaka, N., et al., Input-output organization of jaw movement-related areas in monkey frontal cortex. J Comp Neurol, 2005. 492(4): p. 401-425.
62Heller L, Hulsteyn DBv (1992) Brain stimulation using electromagnetic sources: theoretical aspects. Biophysical Journal 63:129-138.
63Hinch, E.J., et al., Dielectric response of a dilute suspension of spheres with thin double layers in an asymmetric electrolyte. J Chem Soc, Farady Tans., 1983. 80: p. 535-551.
64Holdefer, R.N., R. Sadleir, and M.J. Russell, Predicted current densities in the brain during transcranial electrical stimulation. Clin Neurophysiol, 2006. 117(6): p. 1388-1397.
65Hole, S. and T. Ditchi, Non-destructive Methods for Space Charge Distribution Measurements: What are the Differences? IEEE EMBS, 2003. 10(4): p. 670-677.
66Hsiao, I. and V. Lin, Improved coil design for functional magnetic stimulation of expiratory muscles. IEEE Trans Biomed Eng, 2001. 48(6): p. 684-694.
67Hsu KH and D. DM., A 3-D differential coil design for localized magnetic stimulation. IEEE Trans Biomed Eng, 2001. 48(10): p. 1162-1168.
68International Search Report dated Mar. 18, 2010 (three pages).
69Jones KE, Bawa P (1997) Computer simulation of the responses of human motoneurons to composite 1A EPSPS: effects of background firing rate. J Neurophysiol 77:405-420.
70Kanai, R., et al., Frequency-dependent electrical stimulation of the visual cortex. Curr Biol, 2008. 18(23): p. 1839-1843.
71Kanner, A.M., Deep brain stimulation for intractable epilepsy: which target and for which seizures? Epilepsy Curr, 2004. 4(6): p. 231-232.
72Kaufman, E.F. and A.C. Rosenquist, Efferent projections of the thalamic intralaminar nuclei in the cat. Brain Res, 1985. 335(2): p. 257-279.
73Khachaturian, M.H., et al., Focal reversible deactivation of cerebral metabolism affects water diffusion. Magn Reson Med, 2008. 60(5): p. 1178-1189.
74Khraiche, M.L., et al., Ultrasound induced increase in excitability of single neurons. Conf Proc IEEE Eng Med Biol Soc, 2008. 2008: p. 4246-4249.
75Kleim, J.A., T.A. Jones, and T. Schallert, Motor enrichment and the induction of plasticity before or after brain injury. Neurochem Res, 2003. 28(11): p. 1757-1769.
76Komissarow, L., et al., Triple stimulation technique (TST) in amyotrophic lateral sclerosis. Clin Neurophysiol, 2004. 115 (2): p. 356-360.
77Kraus, K.H., et al., The use of a cap-shaped coil for transcranial magnetic stimulation of the motor cortex. J Clin Neurophysiol, 1993. 10(3): p. 353-362.
78Kumar, K., C. Toth, and R.K. Nath, Deep brain stimulation for intractable pain: a 15-year experience. Neurosurgery, 1997. 40(4): p. 736-46; discussion 746-7.
79Larkin, J., et al., Combined electric field and ultrasound therapy as a novel anti-tumour treatment. European Journal of Cancer 41 (2005) 1339-1348.
80Lemay, M.A., et al. Endpoint forces obtained during intraspinal microstimulation of the cat lumbar spinal cord-experimental and biomechanical model results. In IEEE 28th Annual Northeast Bioengineering Conference, 2002. 2002: IEEE.
81Lemay, M.A., et al. Endpoint forces obtained during intraspinal microstimulation of the cat lumbar spinal cord—experimental and biomechanical model results. In IEEE 28th Annual Northeast Bioengineering Conference, 2002. 2002: IEEE.
82Li, D.L., et al. Finite element analysis of transcranial electrical stimulation for intraoperative monitoring. in Bioengineering Conference, 2005. Proceedings of the IEEE 31st Annual Northeast 2005: IEEE.
83Lin, V., I. Hsiao, and V. Dhaka, Magnetic coil design considerations for functional magnetic stimulation. IEEE Trans Biomed Eng, 2000. 47(5): p. 600-610.
84Lomber, S.G., The advantages and limitations of permanent or reversible deactivation techniques in the assessment of neural function. J Neurosci Methods, 1999. 86(2): p. 109-117.
85Lozano, A.M., et al., Deep brain stimulation for Parkinson's disease: disrupting the disruption. Lancet Neurol, 2002. 1 (4): p. 225-231.
86Luber, B., et al., Remediation of sleep-deprivation-induced working memory impairment with fMRI-guided transcranial magnetic stimulation. Cereb Cortex, 2008. 18(9): p. 2077-2085.
87McCreery D, Agnew W (1990) Neuronal and axonal injury during functional electrical stimulation; a review of the possible mechanisms. In: Annual International Conference of the IEEE Engineering in Medicine and Biology Society, p. 1489: IEEE.
88McCreery, D., et al., Charge Density and Charge Per Phase as Cofactors in Neural Injury Induced by Electrical Stimulation. IEEE Trans Biomed Eng, 1990. 37(10): p. 996-1001.
89McCreery, D., et al.,Accessing the Tonotopic Organization of the Ventral Cochlear Nucleus by Intranuclear Microstimulation. IEEE Trans Rehabil Eng, 1998. 6(4): p. 391-399.
90McIntyre, C.C. and W.M. Grill, Excitation of central nervous system neurons by nonuniform electric fields. Biophys J, 1999. 76(2): p. 878-888.
91McIntyre, C.C. and W.M. Grill, Extracellular stimulation of central neurons: influence of stimulus waveform and frequency on neuronal output. J Neurophysiol, 2002. 88(4): p. 1592-1604.
92McIntyre, C.C., et al., Cellular effects of deep brain stimulation: model-based analysis of activation and inhibition. J Neurophysiol, 2004. 91(4): p. 1457-1469.
93McIntyre, C.C., et al., Electric field and stimulating influence generated by deep brain stimulation of the subthalamic nucleus. Clin Neurophysiol, 2004. 115(3): p. 589-595.
94McNeal DR (1976) Analysis of a model for excitation of myelinated nerve. IEEE Trans Biomed Eng 23:329-337.
95McRee, D.I. and H. Wachtel, Elimination of microwave effects on the vitality of nerves after blockage of active transport. Radiat Res, 1986. 108(3): p. 260-268.
96McRee, D.I. and H. Wachtel, Pulse microwave effects on nerve vitality. Radiat Res, 1982. 91(1): p. 212-218.
97McRee, D.I. and H. Wachtel, the effects of microwave radiation on the vitality of isolated frog sciatic nerves. Radiat Res, 1980. 82(3): p. 536-546.
98Medtronic, Activa PC Implant Manual, Medtronic, Editor. 2007, Medtronic: Minneapolis.
99Mihran, R.T., et al., Temporally-Specific Modification of Myelinated Axon Excitability in Vitro Following a Single Ultrasound Pulse. Ultrasound in Med. & Biol., 1990, vol. 16, No. 3, pp. 297-309.
100Miocinovic, S. and W.M. Grill, Sensitivity of temporal excitation properties to the neuronal element activated by extracellular stimulation. J Neurosci Methods, 2004. 132(1): p. 91-99.
101Miranda, P.C., M. Hallett, and P.J. Basser, The electric field induced in the brain by magnetic stimulation: a 3-D finite-element analysis of the effect of tissue heterogeneity and anisotropy. IEEE Trans Biomed Eng, 2003. 50(9): p. 1074-1085.
102Miranda, P.C., M. Lomarev, and M. Hallett, Modeling the current distribution during transcranial direct current stimulation. Clin Neurophysiol, 2006. 117(7): p. 1623-1629.
103Montalibet, A., et al., Electric current generated by ultrasonically induced Lorentz force in biological media. Med. Biol. Eng. Comput., 2001, vol. 39, pp. 15-20.
104Mouchawar, G., et al., Magnetic Stimulation of excitable tissue: calculation of induced eddy currents with a three-dimensional finite-element model. IEEE Transactions on Magnetics, 1993. 29(6): p. 3355-3357.
105Murasugi, C.M., C.D. Salzman, and W.T. Newsome, Microstimulation in visual area MT: effects of varying pulse amplitude and frequency. J Neurosci, 1993. 13(4): p. 1719-1729.
106Mushahwar, V.K. and K.W. Horch, Selective activation of muscle groups in the feline hindlimb through electrical microstimulation of the ventral lumbo-sacral spinal cord. IEEE Trans Rehabil Eng, 2000. 8(1): p. 11-21.
107Nadeem, M., et al., Computation of electric and magnetic stimulation in human head using the 3-D impedance method. IEEE Transactions on Biomedical Engineering, 2003. 50(7): p. 900-907.
108Nagarajan, S. and D.M. Durand, Analysis of magnetic stimulation of a concentric axon in a nerve bundle. IEEE Transactions on Biomedical Engineering, 1995. 42(9): p. 926-933.
109Nagarajan, S., D.M. Durand, and E.N. Warman, Effects of induced electric fields on finite neuronal structures: a simulation study. IEEE Transactions on Biomedical Engineering, 1993. 40(11): p. 1175-1188.
110Nagarajan, S., et al. Magnetic stimulation of finite neuronal structures. in Annual International Conference of the IEEE Engineering in Medicine and Biology Society. 1991: IEEE.
111Nathan, S.S., et al., Determination of current density distributions generated by electrical stimulation of the human cerebral cortex. Electroencephalogr Clin Neurophysiol, 1993. 86(3): p. 183-192.
112Neri Accornero et al., ‘Visual evoked potentials modulation during direct current cortical polarization’, Experimental Brain Research, Oct. 19, 2006, vol. 178, No. 2, pp. 261-266.
113Neri Accornero et al., 'Visual evoked potentials modulation during direct current cortical polarization', Experimental Brain Research, Oct. 19, 2006, vol. 178, No. 2, pp. 261-266.
114Nichols, M.J. and W.T. Newsome, Middle temporal visual area microstimulation influences veridical judgments of motion direction. J Neurosci, 2002. 22(21): p. 9530-9540.
115NorthstarNeuorsciences, Northstar Neuroscience Announces Primary Endpoint Results of EVEREST Clinical Trial. 2008: Seattle. p. 1.
116Norton, S., BioMedical Engineering OnLine. BioMedical Engineering OnLine 2003, 2:6, pp. 1-9.
117O'Brien, W.D., Jr., Ultrasound-biophysics mechanisms. Prog Biophys Mol Biol, 2007. 93(1-3): p. 212-255.
118Pascual-Leone, A., D. Bartres-Faz, and J.P. Keenan, Transcranial magnetic stimulation: studying the brain-behaviour relationship by induction of ‘virtual lesions’. Philos Trans R Soc Lond B Biol Sci, 1999. 354(1387): p. 1229-1238.
119Pascual-Leone, A., D. Bartres-Faz, and J.P. Keenan, Transcranial magnetic stimulation: studying the brain-behaviour relationship by induction of 'virtual lesions'. Philos Trans R Soc Lond B Biol Sci, 1999. 354(1387): p. 1229-1238.
120Perlmutter, J.S. and J.W. Mink, Deep Brain Stimulation. Annu Rev Neurosci, 2006.
121Pernot, M., et al., In vivo transcranial brain surgery with an ultrasonic time reversal mirror. J Neurosurg, 2007. 106(6): p. 1061-1066.
122Plonsey R, Heppner DB (1967) Considerations of quasi-stationarity in electrophysiological systems. Bull Math Biophys 29:657-664.
123Priori, A., Brain polarization in humans: a reappraisal of an old tool for prolonged non-invasive modulation of brain excitability. Clin Neurophysiol, 2003. 114(4): p. 589-595.
124Prochazka, A., V.K. Mushahwar, and D.B. McCreery, Neural prostheses. J Physiol, 2001. 533(Pt 1): p. 99-109.
125Purpura, D.P. and J.G. McMurtry, Intracellular Activities and Evoked Potential Changes During Polarization of Motor Cortex. J Neurophysiol, 1965. 28: p. 166-185.
126Ramos-Estebanez, C., et al., Visual phosphene perception modulated by subthreshold crossmodal sensory stimulation. J Neurosci, 2007. 27(15): p. 4178-4181.
127Ranck, J.B., Jr., Which elements are excited in electrical stimulation of mammalian central nervous system: a review. Brain Res, 1975. 98(3): p. 417-440.
128Rattay, F., et al., Mechanisms of Electrical Stimulation with Neural Prostheses. Neuromodulation, 2003. 6(1): p. 42-56.
129Rezai, A.R., et al., Deep brain stimulation for Parkinson's disease: surgical issues. Mov Disord, 2006. 21 Suppl 14: p. S197-S218.
130Romo, R., et al., Somatosensory discrimination based on cortical microstimulation. Nature, 1998. 392(6674): p. 387-390.
131Roth, B.J., Mechanisms for electrical stimulation of excitable tissue. Critical Reviews in Biomedical Engineering, 1994. 22(3-4): p. 253-305.
132Rousche, P. and R. Normann, Chronic Intracortical Microstimulation (ICMS) of Cat Sensory Cortex Using the Utah Intracortical Electrode Array. IEEE Trans Rehabil Eng, 1999. 7(1): p. 56-68.
133Rush, S. and D.A. Driscoll, Current distribution in the brain from surface electrodes. Anesth Analg, 1968. 47(6): p. 717-723.
134Rutten, W.L.C., et al., The influence of ultrasound and ultrasonic focusing on magnetic and electric peripheral nerve stimulation., in Advances in Magnetic Stimulation: Mathematical modeling and clinical applications, J. Nilsson, M. Panizza, and F. Grandori, Editors. 1996: Pavia, Italy. p. 152.
135Salzman, C D., K.H. Britten, and W.T. Newsome, Cortical microstimulation influences perceptual judgements of motion direction. Nature, 1990. 346(6280): p. 174-177.
136Salzman, CD., et al., Microstimulation in visual area MT: effects on direction discrimination performance. J Neurosci, 1992. 12(6): p. 2331-2355.
137Saypol, J.M., et al., A theoretical comparison of electric and magnetic stimulation of the brain. Annals of Biomedical Engineering, 1991. 19(3): p. 317-328.
138Schmidt, E.M., et al., Feasibility of a visual prosthesis for the blind based on intracortical microstimulation of the visual cortex. Brain, 1996. 119 ( Pt 2): p. 507-522.
139Schwartzbaum, J.S., Electrophysiology of taste, feeding and reward in lateral hypothalamus of rabbit. Physiol Behav, 1988. 44(4-5): p. 507-526.
140Schwarz, G.J., J Phys Chem, 1962. 66: p. 2636.
141Scivill, I., A.T. Barker, and I.L. Freeston, Finite element modelling of magnetic stimulation of the spine. Proceedings 18th annual international conference of the IEEE engineering in medicine and biology society, 1996: p. 393-394.
142Seidemann, E. and W.T. Newsome, Effect of spatial attention on the responses of area MT neurons. J Neurophysiol, 1999. 81(4): p. 1783-1794.
143Seidemann, E., et al., Color signals in area MT of the macaque monkey. Neuron, 1999. 24(4): p. 911-917.
144Shupak, N.M., et al., Exposure to a specific pulsed low-frequency magnetic field: a double-blind placebo-controlled study of effects on pain ratings in rheumatoid arthritis and fibromyalgia patients. Pain Res Manag, 2006. 11(2): p. 85-90.
145Spiegel, R.J., et al., Measurement of small mechanical vibrations of brain tissue exposed to extremely-low-frequency electric fields. Bioelectromagnetics, 1986. 7(3): p. 295-306.
146Stecker, M.M., T. Patterson, and B.L. Netherton, Mechanisms of electrode induced injury. Part 1: theory. Am J Electroneurodiagnostic Technol, 2006. 46(4): p. 315-342.
147Stojanovic, M.P. and S. Abdi, Spinal cord stimulation. Pain Physician, 2002. 5(2): p. 156-166.
148Stoney, S.D., Jr., W.D. Thompson, and H. Asanuma, Excitation of pyramidal tract cells by intracortical microstimulation: effective extent of stimulating current. J Neurophysiol, 1968. 31(5): p. 659-669.
149Tehovnik, E.J. and W.M. Slocum, Microstimulation of V1 affects the detection of visual targets: manipulation of target contrast. Exp Brain Res, 2005. 165(3): p. 305-314.
150Tehovnik, E.J., Electrical stimulation of neural tissue to evoke behavioral responses. J Neurosci Methods, 1996. 65(1): p. 1-17.
151Terzuolo, C.A. and T.H. Bullock, Measurment of Imposed Voltage Gradient Adequate to Modulate Neuronal Firing. Proc Natl Acad Sci U S A, 1956. 42(9): p. 687-694.
152Thickbroom, G.W., Transcranial magnetic stimulation and synaptic plasticity: experimental framework and human models. Exp Brain Res, 2007. 180(4): p. 583-593.
153Thomas, A.W., D.J. Drost, and F.S. Prato, Human subjects exposed to a specific pulsed (200 microT) magnetic field: effects on normal standing balance. Neurosci Lett, 2001. 297(2): p. 121-124.
154Tofts, P.S., The distribution of induced currents in magnetic stimulation of the nervous system. Physical Medicine and Biology, 1990. 35: p. 1119-1128.
155Tranchina, D. and C. Nicholson, A model for the polarization of neurons by extrinsically applied electric fields. Biophys J, 1986. 50(6): p. 1139-1156.
156Traub RD (1977) Motorneurons of different geometry and the size principle. Biol Cybern 25:163-176.
157Troster, A.I., et al., Neuropsychological deficits in essential tremor: an expression of cerebello-thalamo-cortical pathophysiology? Eur J Neurol, 2002. 9(2): p. 143-151.
158Tyler, W.J., et al., Remote excitation of neuronal circuits using low-intensity, low-frequency ultrasound. PLoS One, 2008. 3(10): p. e3511.
159Ueno, S., T. Tashiro, and K. Harada, Localised stimulation of neural tissues in the brain by means of a paired configuration of time-varying magnetic fields. J. Appl. Phys., 1988. 64: p. 5862-5864.
160Wagner T, Valero-Cabre A, Pascual-Leone A (2007) Noninvasive Human Brain Stimulation. Annu Rev Biomed Eng.
161Wagner TA, Zahn M, Grodzinsky AJ, Pascual-Leone A (2004) Three-dimensional head model simulation of transcranial magnetic stimulation. IEEE Trans Biomed Eng 51:1586-1598.
162Wagner, T., et al., Biophysical foundations underlying TMS: Setting the stage for an effective use of neurostimulation in the cognitive neurosciences. Cortex, 2008.
163Wagner, T., et al., Transcranial direct current stimulation: a computer-based human model study. Neuroimage, 2007. 35(3): p. 1113-1124.
164Wagner, T., et al., Transcranial magnetic stimulation and brain atrophy: a computer-based human brain model study. Exp Brain Res, 2008.
165Wagner, T., et al., Transcranial magnetic stimulation and stroke: a computer-based human model study. Neuroimage, 2006. 30(3): p. 857-870.
166Wagner, T., Field distributions within the human cortex induced by transcranial magnetic stimulation, in EECS. 2001, Massachusetts Institute of Technology: Cambridge. p. 186.
167Warman, E.N., W.M. Grill, and D. Durand, Modeling the effects of electric fields on nerve fibers: determination of excitation thresholds. IEEE Trans Biomed Eng, 1992. 39(12): p. 1244-1254.
168Wichmann, T. and M.R. Delong, Deep brain stimulation for neurologic and neuropsychiatric disorders. Neuron, 2006. 52(1): p. 197-204.
169Wininger, F.A., J.L. Schei, and D.M. Rector, Complete optical neurophysiology: toward optical stimulation and recording of neural tissue. Appl Opt, 2009. 48(10): p. D218-D224.
170Wobschall, D., Bilayer Membrane Elasticity and Dynamic Response. Journal of Colloid and Interface Science, 1971. 36(3): p. 385-396.
171Wobschall, D., Voltage Dependence of Bilayer Membrane Capacitance. Journal of Colloid and Interface Science, 1972. 40(3): p. 417-423.
172Wongsarnpigoon, A. and W.M. Grill, Computational modeling of epidural cortical stimulation. J Neural Eng, 2008. 5(4): p. 443-454.
173Zangen, A., et al., Transcranial magnetic stimulation of deep brain regions: evidence for efficacy of the H-coil. Clin Neurophysiol, 2005. 116(4): p. 775-779.
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